Is RTEL1 p.Pro1254= (c.3762C>T) pathogenic?

RTEL1 p.Pro1254= (c.3762C>T) is classified Likely benign in RTEL1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-15). Ultra-rare (popmax 0.0166%, mid); Associated with dyskeratosis congenita, autosomal recessive 5.

What condition is associated with RTEL1 p.Pro1254= (c.3762C>T)?

RTEL1 p.Pro1254= (c.3762C>T) is associated with dyskeratosis congenita, autosomal recessive 5, pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (ClinVar).

How common is RTEL1 p.Pro1254= (c.3762C>T) in the general population?

RTEL1 p.Pro1254= (c.3762C>T) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

RTEL1 p.Pro1254=

c.3762C>T · rs1412784170 · VCV1102190

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Conditions

dyskeratosis congenita, autosomal recessive 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.05	GERP -2.5, phastCons 0.13
Overall
CADD	14.1	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% Middle Eastern · 1/6,042 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000248% 4/1,612,076 alleles · ultra-rare exomes 4/1,459,750 · genomes 0/152,326 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,042
East Asian	0.00223%	44,886
European (non-Finnish)	0.00017%	589,953

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: RTEL1
Protein: p.Pro1254=
Coding: c.3762C>T
MANE Select: NM_001283009
dbSNP: rs1412784170
Type: single nucleotide variant
Location: chr20:63695590 (GRCh38)
Gene constraint: LOEUF 0.661 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.64 · 3 PDB

Full RTEL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

dyskeratosis congenita, autosomal recessive 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3

Similar variants

RTEL1 p.Pro1254Ala Uncertain significance ★ same residue
RTEL1 p.Pro1254Leu Conflicting classifications of pathogenicity ★ same residue
RTEL1 p.Pro1254Ser Likely benign ★ same residue
RTEL1 p.Pro1254Arg Uncertain significance ★ same residue
RTEL1 c.1037+1G>T Likely pathogenic ★★ same condition
RTEL1 c.1192-2A>G Likely pathogenic ★★ same condition
RTEL1 c.1596-1G>A Likely pathogenic ★★ same condition
RTEL1 c.2142-1G>C Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/rtel1-p-pro1254 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown